The mechanism by which antihistamines protect against digitalis-induced arrhythmias and the role of central histaminergic function in digitalis toxicity will be investigated in guinea pigs. Cimetidine, a histamine H2-receptor antagonist, has been shown in several studies to protect against ouabain-induced arrhythmias and lethality. These protective actions appear to be indirect, resulting from a reduction of sympathetic nervous system effects. Recent experiments demonstrate that efferent cholinergic tone is essential in order for cimetidine to exert protection against digitalis toxicity. These findings are consistent with the hypothesis that H2-antagonists act through a cholinergic mechanism to inhibit indirect, sympathetically mediated components of digitalis toxicity. The ability of cimetidine and ranitidine to augment cholinergic function is suggested in a number of literature reports and will be systematically explored in this project. Experiments will be conducted to evaluate the effects of cimetidine and ranitidine on vagal activity, on responses to electrical stimulation of parasympathetic nerves, and on the direct actions of acetylcholine and related cholinergic stimulants. Studies on the interaction of these compounds with cholinergic mechanisms may provide the key to understanding the way in which they protect against glycoside-induced cardiotoxicity. Histamine is located near cardiovascular control centers in the CNS and exerts modulatory effects on cardiac function mediated through the sympathetic nerves. The role of brain histamine in digitalis toxicity will be explored by making intra-cerebroventricular injections of selective histamine receptor agonists, antagonists, and drugs that alter brain histamine levels, and observing the resultant effects upon the arrhythmogenic and lethal doses of ouabain. From these data, it should be possible to determine for the first time the influence of endogenous brain histamine on digitalis toxicity and the class of receptors involved. These results will aid in understanding the interactions between cardiac glycosides and central neurotransmitters and should give insight into the contribution of histaminergic neurons in the genesis of neurally-mediated arrythmias.